Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center, Rotterdam, 3015 GD, The Netherlands.
Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Acta Neuropathol Commun. 2023 Aug 2;11(1):126. doi: 10.1186/s40478-023-01588-9.
Early pathological features of frontotemporal lobar degeneration (FTLD) due to MAPT pathogenic variants (FTLD-MAPT) are understudied, since early-stage tissue is rarely available. Here, we report unique pathological data from three presymptomatic/early-stage MAPT variant carriers (FTLD Clinical Dementia Rating [FTLD-CDR] = 0-1). We examined neuronal degeneration semi-quantitatively and digitally quantified tau burden in 18 grey matter (9 cortical, 9 subcortical) and 13 white matter (9 cortical, 4 subcortical) regions. We compared presymptomatic/early-stage pathology to an intermediate/end-stage cohort (FTLD-CDR = 2-3) with the same variants (2 L315R, 10 P301L, 6 G272V), and developed a clinicopathological staging model for P301L and G272V variants. The 68-year-old presymptomatic L315R carrier (FTLD-CDR = 0) had limited tau burden morphologically similar to L315R end-stage carriers in middle frontal, antero-inferior temporal, amygdala, (para-)hippocampus and striatum, along with age-related Alzheimer's disease neuropathological change. The 59-year-old prodromal P301L carrier (FTLD-CDR = 0.5) had highest tau burden in anterior cingulate, anterior temporal, middle/superior frontal, and fronto-insular cortex, and amygdala. The 45-year-old early-stage G272V carrier (FTLD-CDR = 1) had highest tau burden in superior frontal and anterior cingulate cortex, subiculum and CA1. The severity and distribution of tau burden showed some regional variability between variants at presymptomatic/early-stage, while neuronal degeneration, mild-to-moderate, was similarly distributed in frontotemporal regions. Early-stage tau burden and neuronal degeneration were both less severe than in intermediate-/end-stage cases. In a subset of regions (10 GM, 8 WM) used for clinicopathological staging, clinical severity correlated strongly with neuronal degeneration (rho = 0.72, p < 0.001), less strongly with GM tau burden (rho = 0.57, p = 0.006), and did not with WM tau burden (p = 0.9). Clinicopathological staging showed variant-specific patterns of early tau pathology and progression across stages. These unique data demonstrate that tau pathology and neuronal degeneration are present already at the presymptomatic/early-stage of FTLD-MAPT, though less severely compared to intermediate/end-stage disease. Moreover, early pathological patterns, especially of tau burden, differ partly between specific MAPT variants.
额颞叶变性（FTLD）的早期病理特征（FTLD-MAPT）由于 MAPT 致病变体（FTLD-MAPT）的研究较少，因为很少有早期组织可用。在这里，我们报告了三位无症状/早期 MAPT 变体携带者（FTLD 临床痴呆评定量表[FTLD-CDR] = 0-1）的独特病理数据。我们对神经元变性进行了半定量检查，并对 18 个灰质（9 个皮质，9 个皮质下）和 13 个白质（9 个皮质，4 个皮质下）区域的 tau 负担进行了数字量化。我们将无症状/早期阶段的病理学与具有相同变体的中间/晚期队列（FTLD-CDR = 2-3）进行了比较（2 个 L315R，10 个 P301L，6 个 G272V），并为 P301L 和 G272V 变体开发了一种临床病理分期模型。这位 68 岁的无症状 L315R 携带者（FTLD-CDR = 0）的 tau 负担形态有限，与中间额叶、前下颞叶、杏仁核、（副）海马和纹状体的 L315R 晚期携带者相似，同时伴有与年龄相关的阿尔茨海默病神经病理学改变。这位 59 岁的前驱性 P301L 携带者（FTLD-CDR = 0.5）的前扣带回、前颞叶、中/额上和额眶皮质以及杏仁核的 tau 负担最高。这位 45 岁的早期 G272V 携带者（FTLD-CDR = 1）的额上和前扣带回皮质、下托和 CA1 的 tau 负担最高。在无症状/早期阶段，tau 负担的严重程度和分布在变体之间存在一定的区域变异性，而神经元变性（轻度至中度）在额颞叶区域的分布相似。与中间/晚期病例相比，早期tau 负担和神经元变性都不那么严重。在用于临床病理分期的一组区域（10 个 GM，8 个 WM）中，临床严重程度与神经元变性（rho = 0.72，p < 0.001）高度相关，与 GM tau 负担（rho = 0.57，p = 0.006）弱相关，与 WM tau 负担无关（p = 0.9）。临床病理分期显示了特定变体在不同阶段的早期 tau 病理学和进展的模式。这些独特的数据表明，tau 病理学和神经元变性已经存在于 FTLD-MAPT 的无症状/早期阶段，尽管与中间/晚期疾病相比，情况不太严重。此外，早期病理模式，尤其是 tau 负担，在特定的 MAPT 变体之间存在部分差异。
